Fluorinated arachidonic acid derivatives

ABSTRACT

Fluorinated arachidonic derivatives are 5-lipoxygenase inhibitors which have the useful pharmacologic activity as antiallergy and anti-inflammatory agents and are useful for treating, for example, asthma, anaphylaxis, allergy, rheumatoid arthritis, and psoriasis and cardiovascular diseases.

This is a continuation of application Ser. No. 07/561,382, filed Apr.30, 1990 now abandoned.

This invention relates to certain fluorinated arachidonic acidderivatives and their pharmaceutical uses.

BACKGROUND OF THE INVENTION

Lipoxygenases, which are found in various mammalian tissues includingthe lung, mast cells, platelets, and white cells, are enzymes whichoxidize arachidonic acid into hydroperoxyeicosatetraenoic acids (HPETEs)which are in turn reduced to the corresponding hydroxyeicosatetra-enoicacids (HETEs). The lipoxygenases are classified according to theposition in the arachidonic acid which is oxygenated. Plateletsmetabolize arachidonic acid to 12-HETE via a 12-lipoxygenase, whilepolymorphonuclear leukocytes contain 5- and 15-lipoxygenases whichoxidize arachidonic acid to 5-HPETE and 15-HPETE, respectively.

5-HPETE is the precursor of leukotriene A₄, an unstable precursor of twodistinct groups of leukotrienes. The first of these are thepeptido-lipid leukotrienes LTC₄ and LTD₄ formed sequentially by reactionof LTA₄ with glutathione followed by reaction with γ-glutamyltrans-peptidase to form the cysteinylglycine adduct. These compoundsaccount for the biologically active material known as the slow reactingsubstances of anaphylaxis (SRS-A).

These leukotrienes are potent smooth muscle contracting agents,particularly effective on smooth muscle but also on other tissues. Theyalso promote mucous production, modulate vascular permeability changesand are potent inflammatory agents in human skin. The leukotrienes arepotent spasmogens of human trachea, bronchus and lung parenchymalstrips. Administered as an aerosol to normal volunteers, leukotrieneshave been found to be about 3800 times more potent than histamineitself. In vitro studies have shown that antigen challenge of human lungor human mast cells results in the production and release of significantamounts of leukotrienes. For these reasons leukotrienes are thought tobe major contributors of the symptoms of asthma and anaphylaxis. Themost important compound of the second group of leukotrienes isleukotriene B₄, a dihydroxy fatty acid. This compound is a potentchemotactic agent for neutrophils and in addition may modulate a numberof other functions of these cells. It also affects other cell types suchas lymphocytes and, for example, is thought to inhibit thephytohemagglutinin-induced elaboration of leukocyte inhibitory factor inT-lymphocytes. Leukotriene B₄ is also a potent hyperalgesic agent invivo and can modulate vascular permeability changes through aneutrophil-dependent mechanism.

Psoriasis is a human skin disease which affects from about 2 to 6 percent of the population but fully adequate therapy remains unavailable.One of the earliest events in the development of psoriatic lesions isthe recruitment of leukocytes to the skin site. In human psoriatic skin,abnormally high levels of free arachidonic acid and lipoxygenaseproducts are found. Among these, leukotriene B₄ has been identified inblister fluid from human psoriatic skin, and when injected into humanskin, leukotriene B₄ induces a pronounced accumulation of neutrophils atthe site of injection. Moreover in humans with stable psoriasis,intralesional injection of 15-(S)-HETE, an inhibitor of 5- and12-lipoxygenases, produces considerable improvement of psoriatic plates.

The leukotrienes are important mediators of inflammatory diseasesthrough their ability to modulate leukocyte and lymphocyte functions.The presence of the leukotrienes is thought to be responsible for manyof the symptoms observed in allergy and rheumatoid arthritis patients.

Applicants have now discovered a novel class of fluorinated arachidonicacid derivatives which are potent inhibitors of 5-lipoxygenase, theenzyme responsible for the conversion of arachidonic acid to theleukotrienes. These new compounds are useful as antiallergic andanti-inflammatory agents in the treatment of asthma, anaphylaxis,allergy, rheumatoid arthritis, psoriasis, and cardiovascular diseases.

SUMMARY OF THE INVENTION

Fluorinated arachidonic derivatives of formula 1: ##STR1## wherein oneof R₅ and R₆ is a fluoro group and the other is a hydrogen or both R₅and R₆ individually are a hydrogen;

one of R₈ and R₉ is a fluoro group and the other is a hydrogen;

X is a C(O)OR' group wherein R' is a hydrogen, a straight chain (C₁-C₆)alkyl group, or

X is a group of the formula --C(O)OCH₂ CH(OR")CH₂ (OR'") wherein R" is along chain fatty acid residue and wherein R"' is a hydrogen or a longchain fatty acid residue, or

X is a --C(O)NH₂ or --C(O)NH(OH) group, or

X is a 1H-tetrazol-5-yl group; and

R is a group of one of the structural formulae ##STR2## wherein R₃ is ahydrogen or a straight chain (C₁ -C₄)alkyl and R₄ is a hydrogen or astraight chain (C₁ -C₆)alkyl and wherein a dotted line indicates anoptional double or triple bond

as well as where X is C(O)OR' and R' is a hydrogen and thepharmaceutically acceptable salts thereof are 5-lipoxygenase inhibitorswhich have the useful pharmacologic activity as antiallergy andanti-inflammatory agents and are useful for treating, for example,asthma, anaphylaxis, allergy, rheumatoid arthritis, psoriasis, andcardiovascular diseases.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention may be described as 8-fluoro-,5,8-difluoro-, 9-fluoro-, and 5,9-difluoro-, and 6,9-difluoro-arachidonic acid derivatives.

The R groups of the compounds of this invention may contain one or moredouble bonds. Any double bonds in the R group of this invention musthave the cis configuration except for the double bond at the 13,14position of the hydroxylated R groups which must be of the transconfiguration. Moreover the carbon atom to which the hydroxy group isattached in the hydroxylated R groups, the 15 carbon atom, is chiral. Ofthose compounds having a hydroxylated R group, applicants prefer thosewith the S configuration at the carbon atom bearing the hydroxy group.

As is true with many classes of pharmacologically active compounds,certain subclasses are preferred. In the compounds of this inventionthose of formula 1 wherein X is a CO₂ H group and wherein X is a groupof the formula --C(O)OCH₂ CH(OR")CH₂ (OR'") wherein R" is a long chainfatty acid residue and wherein R"' is a hydrogen or a long chain fattyacid residue are preferred. Also preferred are those compounds offormula 1 wherein the R group is hydroxylated, especially thosehydroxylated R groups having two double bonds. Additionally preferredare those R groups wherein R₃ is an ethyl group, especially those havingtwo or three double bonds and which correspond to5,8,11,14-eicosatetraenoic acid and 5,8,11,14,17-eicosapentaenoic acid.

Those compounds of this invention wherein X is a group of the formula--C(O)OCH₂ CH(OR")CH₂ (OR"') are analogs of the naturally occuringarachidonic acid containing lipids from which arachidonic acid isreleased in mammals. The groups R" and R'" can be long chain, fatty acidresidues. Suitable long chain, fatty acid residues are those of thenaturally occuring saturated and unsaturated fatty acids as well asanalogs of these naturally occuring fatty acids. The carbon chains ofthe naturally occuring fatty acids are usually unbranched, usuallycontain an even number of carbon atoms, and usually any double bonds areof the cis configuration. Additionally the double bonds of the naturallyoccuring unsaturated fatty acids are never conjugated. However, the longchain, fatty acids of this invention may be branched, may contain an oddnumber of carbon atoms, may contain conjugated double bonds, and mayhave trans configuration. Examples of suitable fatty acids are butyric,caproic, caprylic, capric, lauric, myristic, palmitic, stearic,araohidic, lignoceric, oleic, palmit-oleic, linoleic, γ-linolenic,linolenic, arachidonic 5,8,11,14,17-eicosapentaenoic acids.

The 8-fluoro and 5,8-difluoroarachidonic acid derivatives, that is thosecompounds of formula 1 wherein X is a COOH group and R₈ is a fluorogroup, can be prepared by the oxidation of an aldehyde of formula 2

wherein R and R₅ are as defined in formula 1. The oxidation can beaccomplished by, for example, adding an excess of Jones ##STR3## Reagentto a cooled (0° C.) acetone solution of the aldehyde. The reactionmixture is then allowed to react for about 10 to 30 minutes. Isopropanolis then added to consume excess Jones Reagent nd the acetone solvent isremoved by evaporation on the rotary evaporator. The residue is thenmixed with water and the water mixture is extracted with ethyl acetate.After concentration of the ethyl acetate extracts, flash chromatographyon silica gel eluting with a mixture of ethyl acetate and benzene(15:85) results in the isolation of the desired carboxylic acid.

The formula 2 aldehydes are prepared by treatment of a bromo or chloroderivative of formula 3 ##STR4## wherein Hal is a chloro or bromo groupand R and R₅ are as defined in formula 1. This can be accomplished bytreating a solution of N-allyl-N,N',N"-pentamethylphosphoramide intetrahydrohydrofuran (THF) with one equivalent of n-butyllithium whilemaintaining a temperature of about -78° C. for about 1 hour until anionformation is complete. The formula 3 halide is then added to thesolution of anion and the temperature is allowed to rise to about 0° C.The reaction is complete in about 2 hours and the resulting condensationproduct of formula 3a ##STR5## wherein R and R₅ are as defined informula 1, in an ether solvent such as THF or diethyl ether is thensubjected to acid catalyzed hydrolysis employing a mild acid such as adilute mineral acid such as dilute hydrochloric acid. The hydrolysis iscomplete in about 1 to about 2 hours at room temperature. Isolation bysolvent removal and purification by chromatography on, for example,silica gel eluting with a 25:75 mixture of ethyl acetate and hexaneafforded purified product.

The halide of formula 3 is prepared from the allylic alcohol of formula4 ##STR6## wherein R and R₅ are as defined in formula 1 in any suitableart known procedure. Applicants have prepared the halide derivatives offormula 3 by treatment of the formula 4 alcohol with a slight (e.g. 20%)excess of 1-bromo-N,N,2-trimethylpropenylamine in a cooled (0° C.)methylene chloride solution. The formula 3 halide derivatives can alsobe prepared by stepwise conversion of the alcohol, 4, to its mesylatederivative by treatment with methanesulfonic acid chloride in thepresence of a proton acceptor such pyridine or triethylamine. Subsequenttreatment of the mesyl derivative with a source of bromide or chlorideion such as a brominated or chlorinated ion exchange resin, for example,Amberlyst A26, Br⁻ or Cl⁻ form, results in the desired halide. Thehalogenation reaction utilizing Amberlyst A26 resin will take from 8 to24 hours when performed in refluxing benzene.

The alcohol of formula 4 is prepared by reduction of the correspondingcarboxylic ester of formula 5 ##STR7## wherein R and R₅ are as definedin formula 1 and R" is an alkyl or benzyl group, for example, an ethylgroup. The reduction can be carried out in any conventional mannerreadily known by those skilled in the art for reducing an ester in thepresence of an olefinic bond. Applicants have performed this reductionby treating a solution of an ethyl ester of formula 5 (R" is ethyl) inan ethereal solvent such as THF with a aluminun hydride reducing agentsuch as diisobutylaluminun hydride (DIBAL). Such a reaction is typicallycarried out by adding a solution of DIBAL in hexane to a solution of theester in the ethereal solvent. After stirring for from about 15 minutesto about 1 hour, preferably about 30 minutes, the reaction is allowed tocontinue at room temperature for from about 6 to about 24 hours.Addition of methanol to destroy excess reducing agent and ammoniumchloride to precipitate the aluminum salts gives a solution of thereduced product. The product is isolated after solvent removal and ispurified by flash chromatography on silica gel eluting with, forexample, an 8:2 mixute of hexane and ethyl acetate.

The formula 5 ester is prepared from the formula 6 aldehyde ##STR8##wherein R is as defined in formula 1 by reaction with the ylid oftriethylphosphono fluoroacetate.

The ylid is formed from the optionally fluorinated phosphonate in theusual way by treatment of the phosphonate with about one molarequivalent of a strong, organic base, preferably lithiumdiisopropylamide (LDA) formed in situ by the reaction of n-butyl lithiumand diisopropylamine, at low temperature, typically from about -78° C.to about -25° C., in a suitable solvent, preferably a solvent or solventcombination known to promote the Wittig reaction such as tetrahydrofuran(THF). Hexamethylphosphorictriamide (HMPA), which is known to promotethe Wittig reaction by forming a chelate with the lithium counterion,can advantageously be added. The solution of ylid is then allowed towarm slightly to from about -30° C. to about 0° C. and the appropriatealdehyde is added, preferably dropwise, and allowed to react untilformation of the desired condensation product of formula 5 is formed.The product can be isolated by quenching the reaction mixture with asaturated, aqueous solution of ammonium chloride and subsequent removalof the organic solvent by evaporation with a rotary evaporator. Themixture is then extracted with diethyl ether to give the isolatedproduct upon evaporation of the ether solvent. The crude product can bepurified by, for example, flash chromatography on silicagel eluting witha mixture of hexane and bezene (9:1).

The structure 6 aldehyde is in turn prepared from the appropriatedithiane of structure 7 ##STR9## wherein R is as defined in formula 1 byhydrolysis in the usual manner. The dithiane is prepared from theappropriate bromo or chloro of structure 8 ##STR10## wherein R is asdefined in formula 1 and wherein Hal is a bromo or chloro group byreaction with the anion of 1,3-dithiane formed by treatment with n-butyllithium in cooled (i.e., -30° C.) tetrahydrofuran.

The formula 8 halide is prepared from the corresponding alcohol offormula 8a in any suitable art-known manner. Applicants have transformedthe formula 8a alcohol to the formula 8 halide by reaction with oneequivalent of 1-bromo-N,N,2-trimethylpropenylamine in a cooled (0° C.)methylene chloride solution. Alternatively, the formula 7 dithianederivative can be prepared from an activated derivative of the formula8a alcohol such as the mesyl or tosyl derivative of the alcohol.

The formula 8a alcohol can be prepared by reduction of the appropriateester of formula 9 ##STR11## wherein R is as defined for formula 1 andwherein R" is a lower alkyl, phenyl, or benzyl group. This reduction canbe accomplished in any suitable manner such as by treating a solution ofan ethyl ester of formula 9 (R"=ethyl) in an ethereal solvent such asTHF with an aluminum hydride reducing agent such as diisobutylaluminumhydride (DIBAL). Such a rection is typically carried out by adding asolution of DIBAL in hexane to a solution of the ester in the etherealsolvent. After stirring for from about 15 minutes to about 1 hour,preferably about 30 minutes, the reaction is allowed to continue at roomtemperature for from about 6 to about 24 hours. Addition of methanol todestroy excess reducing agent and ammonium chloride to precipitate thealuminum salts gives a solution of the reduced product. The product isisolated after solvent removal and is purified by flash chromatographyon silica gel eluting with, for example, an 8:2 mixture of hexane andethyl acetate.

The formula 9 ester is prepared by the condensation of the ylid of thefluorinated phosphonate (C₂ H₅ O)₂ P(O)CHFCO₂ (C₂ H₅) with an aldehydeof the formula RCHO wherein R is also as defined as above in formula 1.The ylid is formed from the fluorinated phosphonate in the usual way bytreatment of the phosphonate with about one molar equivalent of astrong, organic base, preferably lithium diisopropylamide (LDA) formedin situ by the reaction of n-butyl lithium and diisopropylamine, at lowtemperature, typically from about -78° C. to about -25° C., in asuitable solvent, preferably a solvent or solvent combination known topromote the Wittig reaction such as tetrahydrofuran (THF).Hexamethylphosphorictriamide (HMPA), which is known to promote theWittig reaction by forming a chelate with the lithium counterion, canadvantageously be added. The solution of ylid is then allowed to warmslightly to from about -30° C. to about 0° C. and the appropriatealdehyde is added, preferably dropwise, and allowed to react untilformation of the desired condensation product of formula 9 is formed.The product can be isolated by quenching the reaction mixture with asaturated, aqueous solution of ammonium chloride and subsequent removalof the organic solvent by evaporation with a rotary evaporator. Themixture is then extracted with diethyl ether to give the isolatedproduct upon evaporation of the ether solvent. The crude product can bepurified by, for example, flash chromatography on silicagel eluting witha mixture of hexane and benzene (9:1).

The aldehydes of the formula RCHO, i.e., R is a C₁₁ carbon chain used toprepare the compounds of this invention can be easily prepared fromreadily available materials, for example, from the correspondingalcohols by simple oxidation using pyridinium chlorochromate or Collin'sreagent in methylene chloride. Many of the alcohols and aldehydes areknown. 6-Dodecyn-1-ol is known from J. Chem. Soc., 4363 (1963);(Z)-6-Dodecenal is known from U.S. Pat. No. 4,239,756, granted December1980; (Z,Z)-3,6-dodecedienal is known from Agric. Biol. Chem., 41, 1481(1977); and 1-hydroxy-3,6,9-dodecatriyne and(Z,Z,Z)-1-hydroxy-3,6,9-dodecatriene are known from Tetrahedron Letters,22, 4729 (1981). Olefinic alcohols having the (Z) configuration, forexample, can be prepared by Nickel boride with ethylene diamine inmethanol or ethanol hydrogenation of the corresponding acetylenicalcohols by the procedure of C. A. Brown and V. K. Ahuja, Chemical Comm.553 (1973).

The optically active aldehyde (25) required to prepare those compoundsof formula 1 wherein the R group has the structural formula: ##STR12##can be prepared from D-arabinose as illustrated in Scheme 3. ##STR13##

The thioacetal (26) is first prepared from D-arabinose by the proceduredescribed by M. Wong and G. Gray, J. Amer. Chem. Soc. 100, 3548 (1978).The silyloxy aldehyde (27) is then prepared by reaction of thedithioacetal (26) with mercuric oxide and calcium carbonate in refluxingaqueous acetonitrile. The silyloxy aldehyde (27) is then reacted withthe ylid of n-propylbromide and triphenylphosphine (28) formed in theusual manner by reaction with a strong base such as n-butyllithium andpotassium t-butoxide in a solvent such as tetahydrofuran. The resultingsilyloxyolefin (29) is reduced catalytically with, for example,molecular hydrogen and a palladium on carbon catalyst in ethylacetate toform the silyloxy compound (30). The silyloxy compound (30) is convertedto the unsaturated aldehyde (33) by the procedure described in G. Justand Z. Wang, Tet. Lett. 26, 2993 (1985) via the diol (31) and thealdehyde (32). Reaction of the unsaturated aldehyde (33) with the ylidof the acetone ketal of 3,4-dihydroxyiodobutane described by P. DeClercyand R. Mijnheen, Bull. Soc. chem. Belg. 87, 495 (1978) in the usualmanner results in the diolefinketal (34). Hydrolysis and sodiummetaperiodate oxidation in a manner analogous to that described for theconversion of (30) to (32) gives the silyl ether derivative (24a) whichupon removal of the silyl group in the usual manner such as by treatmentwith fluoride ion gives the desired diunsaturated aldehyde (24) whereinthe carbon atom bearing the hydroxy group is of the S configuration.Modification of this procedure or chemical modification of thediunsaturated aldehyde can give the other required optically activealdehydes.

In the preparation of the 8-fluoro compounds embraced by formula 1, thesynthesis is affected by the following reaction scheme using compounds 6as starting materials. ##STR14##

The 5,9-difluoroarachidonic acid derivatives, that is those compounds offormula 1 wherein X is a COOH group and R₅ and R₉ are both a fluorogroup, can be prepared by the oxidation of the corresponding alcohol offormula 10 ##STR15## wherein R and R₅ are as defined in formula 1. Suchan oxidation can be accomplished by, for example, treatment of thealcohol with the Jones Reagent. Excess Jones Reagent is then added to acooled (0° C.) acetone solution of the alcohol and the reaction mixtureis then allowed to react for about 10 to 30 minutes. Isopropanol is thenadded to consume excess Jones Reagent and the acetone solvent is removedby evaporation on the rotary evaporator. The residue is then mixed withwater and the water mixture is extracted with ethyl acetate. Afterconcentration of the ethyl acetate extracts, flash chromatography onsilica gel eluting with a mixture of ethyl acetate and benzene (15:85)results in the isolation of the desired carboxylic acid.

The formula 10 alcohol is in turn prepared from the silylated halide offormula 11 ##STR16## wherein R₅ is as defined in formula 1 and Hal is achloro or preferably a bromo group. The formula 11 halide is firstreacted with triphenylphosphine in the usual manner to form thetriphenylphosphonium salt. The ylid is formed from the correspondingphosphonium salt in the usual way by treatment of the phosphonium saltwith about one molar equivalent of a strong, organic base, preferablylithium diisopropylamide (LDA) formed in situ by the reaction of n-butyllithium and diisopropylamine, at low temperature, typically from about-78° C. to about -25° C., in a suitable solvent, preferably a solvent orsolvent combination known to promote the Wittig reaction such astetrahydrofuran (THF). Hexamethylphosphorictriamide (HMPA), which isknown to promote the Wittig reaction by forming a chelate with thelithium counterion, can advantageously be added. The solution of ylid isthen allowed to warm slightly to from about -30° C. to about 0° C. andthe appropriate aldehyde is added, preferably dropwise, and allowed toreact until formation of the desired condensation product is formed. Theproduct can be isolated by quenching the reaction mixture with asaturated, aqueous solution of ammonium chloride and subsequent removalof the organic solvent by evaporation with a rotary evaporator. Themixture is then extracted with diethyl ether to give the isolatedproduct upon evaporation of the ether solvent. The crude product can bepurified by, for example, flash chromatography on silicagel eluting witha mixture of hexane and bezene (9:1). Removal of the diphenyl-t-butylsilyl protecting group in the usual manner such as by treatment withfluoride ion results in the desired formula 10 alcohol.

The formula 11 silylated halide is prepared from the correspondingalcohol of formula 11a wherein R₅ is as defined in formula 1. Applicantshave transformed the alcohol to the halide by reaction with oneequivalent of 1-bromo-N,N,2-trimethylpropenylamine in a cooled (0° C.)methylene chloride solution. The formula 11a alcohol is prepared fromthe corresponding halide of formula 12 ##STR17## wherein R₅ is asdefined in formula 1 and wherein Hal is a chloro group or preferably abromo group. The formula 12 halide is treated with the anion of1,3-dithiane formed by reaction of 1,3-dithiane with n-butyl lithium incooled (i.e. -30° C.) tetrahydrofuran to produce an intermediatedithialane compound which upon hydrolysis in the usual manner such as byaddition of the dithialane derivative to a suspension of one equivalentof trimethyloxonium tetrafluoroborate in methylene chloride. Afterreaction for about one hour at room temperature, two equivalents ofcalcium carbonate in aqueous acetone suspension is added and allowed toreact overnight. The intermediate aldehyde is isolated and reduced with,for example, sodium borohydride in the usual manner to yield the desiredalcohol of formula 11a.

The formula 12 halide is prepared from the corresponding alcohol offormula 12a wherein R₅ is as defined in formula 1 in any suitable artknown procedure. Applicants have prepared the formula 12 bromide bytreatment of the alcohol with one equivalent of1-bromo-N,N-2-trimethylpropenylamine in a cooled (0° C.) methylenechloride solution. Alternatively the formula 12 halide can be preparedby stepwise conversion of the formula 12a alcohol to its mesylate (ortosyl) derivative by treatment with methanesulfonic acid chloride in thepresence of a proton acceptor such pyridine or triethylamine. Subsequenttreatment of the mesyl derivative with a source of bromide ion such as abrominated ion exchange resin, for example, Amberlyst A26, Br⁻ form,results in the desired bromide 12. The bromination reaction utilizingAmberlyst A26 resin will take from 8 to 24 hours when performed inrefluxing benzene. Alternatively, the mesyl (or tosyl) derivative can beutilized directly in the reaction with the anion of 1,3-dithiane toproduce the dithiane intermediate described above for the preparation ofthe formula 11 alcohol.

The formula 12a alcohol is prepared from the ester of formula 13##STR18## wherein R₆ is as defined in formula 1 and wherein R" is alower alkyl, phenyl, or benzyl group such as an ethyl group. Thisreduction can be accomplished in any suitable manner such as by treatinga solution of an ethyl ester of formula 13 (R"=ethyl) in an etherealsolvent such as THF with an aluminum hydride reducing agent such asdiisobutylaluminum hydride (DIBAL). Such a reaction is typically carriedout by adding a solution of DIBAL in hexane to a solution of the esterin the ethereal solvent. After stirring for from about 15 minutes toabout 1 hour, preferably about 30 minutes, the reaction is allowed tocontinue at room temperature for from about 6 to about 24 hours.Addition of methanol to destroy excess reducing agent and ammoniumchloride to precipitate the aluminum salts gives a solution of thereduced product. The product is isolated after solvent removal and ispurified by flash chromatography on silica gel eluting with, forexample, an 8:2 mixute of hexane and ethyl acetate.

The formula 13 ester is in turn prepared reacting the formula 14aldehyde ##STR19## wherein R₅ is as defined in formula 1 with the ylidof the fluorinated phosphonate ester (C₂ H₅ O)₂ P(O)CHFCO₂ C₂ H₅. Theylid is formed from the corresponding phosphonium salt in the usual wayby treatment of the phosphonium salt with about one molar equivalent ofa strong, organic base, preferably lithium diisopropylamide (LDA) formedin situ by the reaction of n-butyl lithium and diisopropylamine, at lowtemperature, typically from about -78° C. to about -25° C., in asuitable solvent preferably a solvent or solvent combination known topromote the Wittig reaction such as tetrahydrofuran (THF).Hexamethylphosphorictriamide (HMPA), which is known to promote theWittig reaction by forming a chelate with the lithium counterion, canadvantageously be added. The solution of ylid is then allowed to warmslightly to from about -30° C. to about 0° C. and the appropriatealdehyde is added, preferably dropwise, and allowed to react untilformation of the desired condensation product of structure 3 is formed.The product can be isolated by quenching the reaction mixture with asaturated, aqueous solution of ammonium chloride and subsequent removalof the organic solvent by evaporation with a rotary evaporator. Themixture is then extracted with diethyl ether to give the isolatedproduct upon evaporation of the ether solvent. The crude product can bepurified by, for example, flash chromatography on silicagel eluting witha mixture of hexane and benzene (9:1).

The formula 14 alcohols are prepared by addition of the 1,3-dithialanederivative of formula 15 to a suspension of one equivalent oftrimethyloxonium tetrafluoroborate in methylene chloride. After reactionfor about one hour at room temperature, two equivalents of calciumcarbonate in aqueous acetone suspension is added and allowed to reactovernight. The aldehyde is isolated by, for example, filtration andsolvent removal.

The silylated dithialanes of formula 15 wherein R₅ is a fluoro group areprepared from the dithianyl alcohol of formula 19 as outlined inscheme 1. ##STR20##

The hydroxy group of the formula 19 butene is converted to a chlorogroup by reaction with, for example, 1-chloro-N,N-2-trimethylpropene.The chlorinated compound of formula 18 wherein R₅ is as defined informula 1 is transformed into the aldehyde of formula 17 by reactionwith N-allyl-N,N',N"-pentamethylphsophoramide in tetrahydrofuran.Reduction in the usual manner with sodium borohydride results information of the alcohol of formula 16. Treatment of the alcohol witht-butyldiphenylsilyl chloride in the presence of a proton acceptor givesthe desired compound of formula 15. The hydroxy, dithialane of formula19 is prepared from a chloro, tetrahydropyranyloxy butene of formula 21##STR21## wherein R₅ is a defined in formula 1. The dithialanederivative of formula 20 ##STR22## is first prepared by reaction of theformula 21 chloro derivative with the anion of 1,3-dithiane formed byreaction with n-butyl lithium in cooled (i.e. -30° C.) tetrahydrofuran.Subsequent removal of the THP protecting group by treatment withmethanol and pyridinium paratoluene sulfonate (PPTS) catalyst results inthe desired formula 19 alcohol. The compound of formula 21 is readilyprepared from the optionally fluorinated maleic acid, formula 24, asillustrated in scheme 2. ##STR23## The optionally fluorinated maleicacid is converted to the corresponding dimethylester of formula 22 byreaction with diazomethane. Subsequent ester group reduction with excessdiisobutylaluminun hydride (DIBAL) in THF at about 0° C. results information of the di-alcohol derivative of formula 23. Selectiveconversion of one of the hydroxy groups can be accomplished using aslight (10%) molar excess of N-chlorosuccinimide (NCS) anddimethylsulfide. Protection of the other hydroxy group as the THPderivative can be accomplished in the usual manner by reaction withdihydropyran (DHP) and catalytic pyridinium paratoluene sulfonate (PPTS)results in formation of the desired formula 21 compound. ##STR24##

To prepare the 6,9-difluoroarachidonic acids of formula 1, the alcoholsof 36 are treated with one equivalent of1-bromo-N,N-2-trimethylpropenylamine in a cooled (0° C.) methylenechloride solution to obtain the corresponding bromide. The bromide (35)is treated with the anion of 1,3-dithiane with n-butyl lithium in cooled(-30° C.) THF to produce an intermediate dithalane which upon hydrolysisin the usual manner (i.e., addition of trimethyloxoniumtetrafluoroborate in CH₂ Cl₂. After reaction for about 1 hour at roomtemperature, two equivalents of calcium carbonate in aqueous acetonesuspension is added and allowed to react overnight.) gives thecorresponding aldehyde. This so-produced 6-F aldehyde is isolated andmay be used without purification. This 6-F aldehyde is converted to thecorresponding 6,9-difluoro compounds in the analogous way that thecorresponding 5-fluoro aldehyde is converted to the 5,9-difluorocompounds of formula 10.

To prepare the 9-fluoro arachidonic acid derivatives of formula 1 thechemistry used and described herein may analogously be utilized.Starting with dehydro-2,3-delta valero lactone, ##STR25## The lactone isreduced to the corresponding 2-diol with an excess of DIBAL in THF. Thediol (HOCH₂ CH₂ CH═CHCH₂ OH) is treated with one equivalent ofN-chlorosuccinimide (NCS) in CH₂ Cl₂ in the presence of dimethylsulfideto yield the Z-1-chloro-5-OH-2-pentene, the alcohol of which isprotected as a tetrahydropyranyl ether (OTHP) using an excess ofdihydropyran in the presence of catalytic amounts of PPTS. The chloride(THPO-CH₂ CH₂ CH═CHCH₂ Cl) is converted to its aldehyde using analogouschemistry as described for converting 3 to 2 (i.e.,[(CH₃)N]2P(O)N(CH₃)(C₃ H₅) plus n-BuLi, (2) HCl and (3) reprotection ofthe alcohol with DHP/PPTS as in the conversion of 16 to 15. The aldehydeis reduced with NaBH₄ (analogously with 17 to 16). The alcohol issilylated using chemistry analogous to conversion of 16 to 15 and thenthe THP ether is cleaned as described on for converting copound 37 to36. The resulting alcohol is oxidized with pyridinium chlorochromate inCH₂ Cl₂, as previously described, to yield the aldehyde which is treatedwith the ylid of a fluorinated phosphonate ester using the samechemistry analogously described for converting compound 14 to 13.Following this chemical step then the same chemistry used to convert 10to the desired arachidonic acids may be used (i.e., the R₅ would be H).

The compounds of structure 1 wherein X is other than C(O)OH can bereadily prepared from the carboxylic acids by any procedure generallyknown to those skilled in the art. For example, those compounds offormula 1 wherein X is --C(O)NH₂, are prepared from the correspondingcompound wherein X is --CO₂ H, by reaction with about 1 molar equivalentof carbonyldiimidazole in an aprotic organic solvent, preferablydichloromethane, for a period of 1 to 7 hours, preferably about 4 hours.Then the product is reacted with a large excess of ammonium hydroxidefor from 24 to 64 hours, preferably for about 48 hours. Isolation of thedesired compounds of formula those in the art.

Alternatively, the compounds of formula 1 wherein X is CONH₂ can beprepared by first converting the acid into an activated derivative suchas, for example, by reaction of the carboxylic acid with an acyl halide,an anhydride, a mixed anhydride, an alkyl ester, a substituted orunsubstituted phenyl ester, a thioalkyl ester, a thiophenyl ester, anacyl imidazole, and the like. The activated derivative is then reactedwith ammonia or aqueous ammonia with or without a suitablewater-miscible or immiscible organic solvent, for example, methanol,ethanol, dichloromethane, and the like, so as to produce the amide. Thereaction is conducted at from -30° C. to the boiling point of thesolvent or solvent mixture used, for from 1 to 96 hours.

Alternatively, the amide can be made by heating together the appropriatecompound of formula 1 wherein X is CO₂ H and ammonia, or by heating theammonium salt of a carboxylic acid of formula 1. The reaction isconducted either in the absence of a solvent, or in the presence of asolvent such as, for example, toluene, at a temperature of from 100° C.to 300° C., for from 1 to 12 hours.

Alternatively, the amide can be obtained by hydrolysis of a nitrilederivative (formula 1 wherein X is CN) using either inorganic or organicacids or bases, such as, for example, hydrochloric acid, sulphuric acid,p-toluenesulphonic acid, sodium hydroxide, potassium carbonate, ortetrabutylammonium hydroxide and the like. The reaction is conducted inwater optionally containing from 1% to 95% of a cosolvent such as, forexample, methanol, acetic acid or diglyme, at a temperature of from 0°C. to the boiling point of the solvent used, for from 1 to 96 hours.Such procedures are well known to those skilled in the art and aredescribed, for example, in Synthetic Organic Chemistry, John Wiley andSons, Publ., New York, 565-590 (1953) and Compendium of OrganicSynthetic Methods, Vol. 1, Wiley-Interscience, New York, 203-230 (1971).

The compounds of formula 1 wherein X is a 1H-tetrazol-5-yl group can beprepared from the corresponding amide (I wherein X is CONH₂) via anintermediate nitrile (I wherein X is CN) derivative. To a solution of anappropriate compound of formula 1 wherein X is CONH₂ in a basic organicsolvent, preferably pyridine, is added about 1 mole, or equivalent, ofan organic sulphonyl halide, preferably p-toluenesulphonyl chloride. Themixture is reacted for 12-48 hours, preferably about 24 hours, and thesolution is poured into water. The nitrile is extracted from the aqueousphase with an organic solvent, preferably ethyl ether, and the extractis purified by procedures known in the art.

The isolated nitrile is then reacted with an excess, preferably 3 moles,of an alkali metal azide, preferably sodium azide, and an excess,preferably 3 moles, of an ammonium halide, preferably ammonium chloride,in an aprotic, polar solvent, preferably dimethylformamide, at atemperature of 80° C. to 120° C., preferably 100° C., for 16 to 48hours, preferably 24 hours optionally in the presence of a Lewis acidsuch as, for example, boron trifluoride. In this reaction, other sourcesof azide ion may be used, such as aluminium azide and the azide oftri-n-butyl tin. The product is then isolated by procedures known in theart.

Alternatively, the compounds of formula 1 wherein X is a1H-tetrazol-5-yl group can be prepared by the reaction between animinoether derivative of formula 1 wherein X═C(NH)O(C₁ -C₆ alkyl) andhydrazoic acid as described in German Patent 521870. The iminoetherderivative is obtained by treatment of a nitrile derivative (formula 1wherein X═CN) with a (C₁ -C₆) alkanol and a strong acid such as, forexample, hydrochloric acid or p-toluenesulphonic acid. The reactionbetween the iminoether and hydrazoic acid is conducted in the presenceof a solvent such as, for example, chloroform or dimethylformamide, atfrom 0° C. to 120° C., for from 1 to 72 hours. Tetrazole derivatives canalso be obtained by the reaction between an amidine derivative of anunsaturated fatty acid, prepared, for example, from the nitrilederivative as described in Synthetic Organic Chemistry, John Wiley andSons, Publ., New York, 635 (1953) and nitrous acid, as described inAnnalen, 263, 96 (1981), and 208, 91 (1987). The reaction is conductedin water or a mixture of water and a suitable organic solvent such as,for example, methanol or dioxane, at from 0° C. to 100° C., for from 1to 24 hours.

The esters of compounds of formula I, those wherein X is C(O)OR¹ whereinR¹ is a straight chain (C₁ -C₆) alkyl group can be prepared in the usualmanner by esterification of the corresponding carboxylic acid of formula1 (X═CO₂ H)by treatment with a solution of hydrogen chloride in theappropriate lower alkanol, preferably the esters are prepared from thecarboxylic acids via the acid chloride derivative. The acid is reactedwith a thionyl or phosphoryl halide or phosphorus pentahalide,preferably thionyl chloride, dissolved in an inert organic solvent,preferably benzene, containing a trace of a tertiary organic amide,preferably dimethylformamide. The mixture is reacted for 8-32 hours,preferably for about 16 hours, at from 0° C. to 25° C., then evaporatedto dryness. The residue, the acid chloride, is dissolved in an inertorganic solvent and the appropriate lower alkanol is added dropwise.

The acylhydroxylamine derivatives, those compounds of formula I whereinX is CONHOH, are prepared in two ways. The acid is either firstconverted, as described above, into the acid chloride or into a loweralkyl ester, preferably the methyl ester. The acid chloride or the loweralkyl ester is then reacted with an excess of hydroxylamine in anaqueous organic solvent, preferably aqueous methanol, at a pH of between7 and 10, preferably at about pH 9, for from 1/4 to 6 hours, preferablyabout 1 hour. The acylhydroxylamine product is then isolated by meansknown in the art.

Acylhydroxylamines can also be prepared by the reaction betweenhydroxylamine and an activated derivative of an unsaturated fatty acidsuch as, for example, an acyl halide, an anhydride, a mixed anhydride,an alkyl ester, a substituted or unsubstituted phenyl ester, a thioalkylester, a thiophenyl ester, an acyl imidazole, and the like. The reactionis conducted in an aqueous organic or organic solvent such as, forexample, methanol, acetonitrile or acetone, at from 0° C. to the refluxtemperature of the solvent, for from 1 to 48 hours. Alternately,acylhydroxylamines can be prepared by acid-catalyzed rearrangement of aprimary nitro derivative (formula 1, X═NO₂) as described in ChemicalReviews, 32, 395 (1943). The reaction is conducted in an aqueous organicor organic solvent, such as, for example, methanol, ethanol and dioxan,at from 0° C. to 100° C., for from 1 to 24 hours, in the presence of astrong acid such as, for example, sulphuric acid or hydrochloric acid.Acylhydroxylamine derivatives of unsaturated fatty acids can also beobtained by the oxidation of the oxime derivative of formula 1 whereinX═CHNOH using, for example, hydrogen peroxide as described in ChemicalReviews, 33, 225 (1943). The reaction is conducted in a solvent such asmethanol or dichloromethane and the like, at from 0° C. to 35° C. forfrom 1 to 6 hours.

The chloro derivative, 17, is first reacted withN-allyl-N,N',N"-pentamethylphosphoramide in tetra-hydrofuran. Theintermediate product is isolated and then treated with concentratedhydrochloric acid. Finally the THP (tetrahydropyranyloxy) group isreformed by reaction of the product with dihydropyran (DHP) andcatalytic pyridinium paratoluene sulfonate (PPTS) to produce thealdehyde, 16. Reduction in the usual manner with sodium borohydrideresults in alcohol 15. Treatment of the alcohol witht-butyldiphenylsilyl chloride in the presence of a proton acceptor givesthe desired 14. The THP protecting group is then removed by treatmentwith methanol and tetrabutyl-1,3-diisothiocyanotodistannoxane catalystto give the alcohol 13. The alcohol is converted to the correspondingbromide, 12, by reaction with 1-bromo-N,N',2-trimethylpropenylamine inmethylene chloride solution. The silylated, dithialane, 7, is thenproduced by reaction of the bromide, 12, with the anion of 1,3-dithianeformed by reaction with n-butyl lithium in cooled (i.e. -30° C.)tetrahydrofuran.

Isolation and purification of the compounds and intermediates describedherein can be effected, if desired, by any suitable separation orpurification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography orthick layer chromatography, or a combination of these procedures.Specific illustrations or suitable separation and isolation procedurescan be had by reference to the examples hereinbelow. However, otherequivalent separation or isolation proceudres could, of course, also beused.

The pharmaceutically acceptable salts of the compounds of this inventionwherein X is CO₂ H, C(O)NHOH or 1H-tetrazol-5-yl, are prepared bytreating the carboxylic acid, acylhydroxylamine or tetrazole compound offormula 1 with at least one molar equivalent of a pharmaceuticallyacceptable base. Representative pharmaceutically acceptable bases aresodium hydroxide, potassium hydroxide, ammonium hydroxide, calciumhydroxide, metal alkoxides, for example, sodium methoxide,trimethylamine, lysine, caffeine, and the like. The reaction isconducted in water, alone or in combination with an inert,water-miscible organic solvent, or in a suitable organic solvent such asmethanol, ethanol, and the like, at a temperature of from about 0° C. toabout 100° C., preferably at room temperature. Typical inert,water-miscible organic solvents include methanol, ethanol, or dioxane.The molar ratios of compounds of Formula 1 to base used are chosen toprovide the ratio desired for any particular salt.

Salts derived from inorganic bases include sodium, potassium, lithium,ammonium, calcium, magnesium, ferrous, zinc, copper, manganous,aluminum, ferric, manganic salts and the like. Particularly preferredare the ammonium, potassium, sodium, calcium and magnesium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic non-toxic bases are isopropylamine, diethylamine, ethanolamine,tromethamine, dicyclohexylamine, choline and caffeine.

The salt products are also isolated by conventional means. For example,the reaction mixtures may be evaporated to dryness, and the salts can befurther purified by conventional methods. Salts of the compounds offormula 1 may be interchanged by taking advantage of differentialsolubilities of the salts, or by treating with the appropriately loadedion exchange resin.

The amount of a fluorinated arachidonic acid derivative of thisinvention necessary to control the biosynthesis of leukotrienesprophylacticly or to treat existing allergic or inflammatory states canvary widely according to the particular dosage unit employed, the periodof treatment, the age and sex of the patient treated and the nature andextent of the disorder treated. The total amount of the activeingredient to be administered will generally range from about 1 mg/kg to150 mg/kg and preferably from 3 mg/kg to 25 mg/kg. For example, anaverage 70 kg human patient will require from about 70 mg to about 10 gof active compound per day. A unit dosage may contain from 25 to 500 mgof active ingredient, and can be taken one or more times per day. Theactive compound of formula 1 can be administered with a pharmaceuticalcarrier using conventional dosage unit forms either orally,parenterally, or topically.

The preferred route of administration is oral administration. For oraladministration the compounds can be formulated into solid or liquidpreparations such as capsules, pills, tablets, troches, lozenges, melts,powders, solutions, suspensions, or emulsions. The solid unit dosageforms can be a capsule which can be of the ordinary hard- orsoft-shelled gelatin type containing, for example, surfactants,lubricants, and inert fillers such as lactose, sucrose, calciumphosphate, and cornstarch. In another embodiment the compounds of thisinvention can be tableted with conventional tablet bases such aslactose, sucrose, and cornstarch in combination with binders such asacacia, cornstarch, or gelatin, disintegrating agents intented to assistthe break-up and dissolution of the tablet following administration suchas potato starch, alginic acid, corn starch, and guar gum, lubricantsintented to improve the flow of tablet granulations and to prevent theadhesion of tablet material to the surfaces of the tablet dies andpunches, for example, talc, stearic acid, or magnesium, calcium, or zincstearate, dyes, coloring agents, and flavoring agents intented toenhance the aesthetic qualities of the tablets and make them moreacceptable to the patient. Suitable excipients for use in oral liquiddosage forms include diluents such as water and alcohols, for example,ethanol, benzyl alcohol, and the polyethylene alcohols, either with orwithout the addition of a pharmaceutically acceptable surfactant,suspending agent, or emulsifying agent.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intramuscularly, orinterperitoneally, as injectable dosages of the compound in aphysiologically acceptable diluent with a pharmaceutical carrier whichcan be a sterile liquid or mixture of liquids such as water, saline,aqueous dextrose and related sugar solutions, an alcohol such asethanol, isopropanol, or hexadecyl alcohol, glycols such as propyleneglycol or polyethylene glycol, glycerol ketals such as2,2-dimethyl-1,3-dioxolane-4-methanol, ethers such aspoly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester orglyceride, or an acetylated fatty acid glyceride with or without theaddition of a pharmaceutically acceptable surfactant such as a soap or adetergent, suspending agent such as pectin, carbomers, methylcellulose,hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifyingagent and other pharmaceutically adjuvants. Illustrative of oils whichcan be used in the parenteral formulations of this invention are thoseof petroleum, animal, vegetable, or synthetic origin, for example,peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, oliveoil, petrolatum, and mineral oil. Suitable fatty acids include oleicacid, stearic acid, and isostearic acid. Suitable fatty acid esters are,for example, ethyl oleate and isopropyl myristate. Suitable soapsinclude fatty alkali metal, ammonium, and triethanolamine salts andsuitable detergents include cationic detergents, for example, dimethyldialkyl ammonium halides, alkyl pyridinum halides, and alkylaminesacetates; anionic detergents, for example, alkyl, aryl, and olefinsulfonates, alkyl, olefin, ether, and monoglyceride sulfates, andsulfosuccinates; nonionic detergents, for example, fatty amine oxides,fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers;and amphoteric detergents, for example, alkyl-beta-aminopropionates, and2-alkylimidazoline quarternary ammonium salts, as well as mixtures. Theparenteral compositions of this invention will typically contain fromabout 0.5 to about 25% by weight of the active ingredient in solution.Preservatives and buffers may also be used advantageously. In order tominimize or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) of from about 12 to about 17. Thequantity of surfactant in such formulations ranges from about 5 to about15% by weight. The surfactant can be a single component having the aboveHLB or can be a mixture of two or more components having the desiredHLB. Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

Aerosol or spray compositions containing the compounds of this inventioncan be applied to the skin or mucous membranes. Such compositions maycontain a micronized solid or a solution of a compound of formula 1 andmay also contain solvents, buffers, surfactants, perfumes,antiumicrobial agents, antioxidants, and propellants. Such compositionsmay be applied by means of a propellant under pressure or may be appliedby means of a compressible plastic spray bottle, a nebulizer, or anatomizer without the use of a gaseous propellent. A preferred aerosol orspray composition is a nasal spray.

The active ingredient may also be administered by means of a sustainedrelease system whereby the compound of formula 1 is gradually releasedat a controlled, uniform rate form an inert or bioerodible carrier bymeans of diffusion, osmosis, or disintegration of the carrier during thetreatment period. Controlled release drug delivery systems may be in theform of a patch or bandage applied to the skin or to the buccal,sublingual, or intranasal membranes, an ocular insert placed in the culde sac of the eye, or a gradually eroding tablet or capsule or agastrointestinal reservoir administered orally. Administration by meansof such sustained release delivery systems permits the tissues of thebody to be exposed constantly for a prolonged time period to atherapeutically or prophylactically effective dosage of a compound offormula 1. The unit dosage of the compound administered by means of asustained release system will approximate the amount of an effectivedaily dosage multiplied by the maximum number of days during which thecarrier is to remains on or in the body of the host. The sustainedrelease carrier may be in the form of a solid or porous matrix orreservoir and may be formed from one or more natural or syntheticpolymers, including modified or unmodified cellulose, starch, gelatin,collagen, rubber, polyolefins, polyamides, polyacrylates, polyalcohols,polyethers, polyesters, polyurethanes, polysulphones, polysiloxanes, andpolyimides as wells as mixtures and copolymers of these polymers. Thecompounds of formula 1 may be incorporated in the sustained releasecarrier in a pure form or may be dissolved in any suitable liquid orsolid vehicle, including the polymer of which the sustained releasecarrier is formed.

EXAMPLE 1 PREPARATION OF 5,8-DIFLUOROEICOSA-5,8,14-TRIENOIC ACID

1A) PREPARATION OF ETHYL 2-FLUOROTETRADECA-2,8-DIENEOATE

n-BuLi 1.7M in hexane solution (12.9 ml) was added at -78° C. to asolution of diisopropylamine (5.5 ml) in tetrahydrofuran. The mixturewas stirred for 20 min. at -78° C. Then triethylphosphorusfluoro acetate(5.3 g, 22 mmoles) in tetrahydrofuran (5 ml) was added dropwise. Themixture was stirred 5 min. at -78° C. and then 20 min. at 0° C. Then6-dodecenal (4 g, 22 mmoles) in tetrahydrofuran (5 mL) was addeddropwise at -78° C. The reaction mixture was stirred overnight at 0° C.The mixture was hydrolyzed with a saturated aqueous solution of ammoniumchloride and extracted with ether. The organic layer was washed withsaturated brine, dried over sodium sulfate and concentrated underreduced pressure. Flash chromatography on silica gel and elution with a8:2 mixture of hexane and ethyl acetate afforded the expected ester asan oil (5.53 g, 93%).

1B) PREPARATION OF 2-FLUOROTETRADECA-2,8-DIENE-OL

The ester prepared in 1A (5.53 g, 20.5 mmoles) in anhydrous ether (5 ml)was added at -78° C. to a mixture of DIBAL, 1M solution in hexane, (61.4ml, 61.5 mmoles) and ether (90 ml). The mixture was stirred 3 min. at-78° C., then overnight at room temperature. The excess of DIBAL wasdestroyed with methanol (10 ml) and the aluminum salts were precipitatedwith an aqueous saturated solution of ammonium chloride (5 ml). Themixture was filtrated and the precipitate washed with ethyl acetate. Thesolvents were evaporated under reduced pressure. Flash chromatographyover silca gel and elution with a 8:2 mixture of hexane and ethylacetate afforded the expected alcohol 2 as an oil (4.52 g, 92%).

1C) PREPARATION OF 1-BROMO-2-FLUOROTETRADECA-2,8-DIENE

The alcohol prepared in 1B (2 g, 8.76 mmoles) was dissolved in drymethylene chloride (20 ml). The mixture was cooled to 0° C. and 1-bromoN,N',2-trimethylpropenyl (1.9 ml, 10.7 mmoles) was added. The mixturewas stirred under argon for 30 min. The methylene chloride wasevaporated under reduced pressure. Flash chromatography on silica geland elution with pentane afforded the expected bromide as an oil (2.55g, 100%).

1D) PREPARATION OF1(1,3-DITHIANE-2-CYCLOHEXYL)-2-FLUOROTETRADECA-2,8-DIENE

To a solution of 1,3-dithiane (1.35 g, 11.12 mmoles) in tetrahydrofuran(50 ml) cooled to -25° C. was added dreopwise a 1.6M solution ofn-butyllithium in hexane (5.8 ml, 9.3 mmoles). The mixture was stirredat -30° C. for 30 min. Then the mixture was cooled to -40° C. and thebromide prepared in 1C (2.72 g, 9.34 mmoles) in tetrahydrofuran (5 ml)was added dropwise. The reaction was stirred 30 min. at -40° C. and 2hrs. at 0° C. The reaction was quenched with saturated aqueous ammoniumchloride and the tetrahydrofuran was evaporated under reduced pressure.The residue was diluted with ether and washed with water. The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. Flash chromatography on silica gel and elution with a8:2 mixture of hexane and ethyl acetate afforded the title dithialane asan oil (2.74 g, 90%).

1E) PREPARATION OF 3-FLUOROPENTADECA-3,9-DIENE-AL

To a solution of the dithialane prepared in 1D (1.5 g, 4.5 mmoles) indry methylene chloride (10 ml) was added at room temperaturetrimethyloxonium tetrafluoroborate (1 g, 6.75 mmoles) and the mixturewas stirred for 1 hr. Then a 9:1 mixture of acetone and water (20 ml)containing calcium carbonate (0.5 g) was added and the mixture wasstirred overnight at room temperature. The precipitate was filtered offand after dilution with saturated brine the mixture was extracted threetimes with ether. The organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure to afford the expectedaldehyde as an oil (650 mg, 60%) which was used without purificationafter drying under high vacuum.

1F) PREPARATION OF 2,5-DIFLUOROHEPTADECA-2,5,11-TRIENE OATE

n-BuLi 1.6M in hexane (1.55 ml) was added at -78° C. tro a solution ofdiisopropyl amine (0.35 mmoles) in tetrahydrofuran. The mixture wasstirred during 20 min. at -78° C. Then triethylphosphonofluoroacetate10.6 g, 2.5 mmoles) in tetrahydrofuran (2 ml) was added dropwise. Themixture was stirred 5 min. at -78° C. and then 20 min. at 0° C. Then thealdehyde prepared in 1E (0.6 g, 2.5 mmoles) in tetrahydrofuran (4 ml)was added dropwise at -78° C. The reaction mixture was stirred overnightat 0° C. The mixture was hydrolyzed with a saturated aqueous solution ofammonium chloride and extracted with ether. The organic layer was washedwith saturated brine, dried over magnesium sulfide and concentratedunder reduced pressure. Flash chromatography on silica gel and elutionwith a 8:2 mixture of hexane and ethyl acetate afforded the expectedester as an oil (0.39 g, 97%).

1G) PREPARATION OF 2,5-DIFLUOROHEPTADECA-2,5-11-TRIENE-OL

The ester prepared in 1F (0.39 g, 1.18 mmoles) in anhydrous ether 5 mlwas added at -78° C. to a mixture of DIBAL, 1M solution in hexane, (2.5mL) and ether (20 ml). The mixture was stirred 30 min. at -78° C., theovernight at room temperature. The excess of DIBAL was destroyed withmethanol (2 ml) and the aluminum salts were precipitated with an aqueoussaturated solution of ammonium chloride. The mixture was filtrated andthe precipitate washed with ethyl acetate. The solvents were evaporatedunder reduced pressure. Flash chromatography over silica gel and elutionwith a 8:2 mixture of hexane and ethyl acetate afforded the expectedalcohol as an oil (0.33 g, 92%).

1H) PREPARATION OF 1-CHLORO-2,5-DIFLUOROHEPTADECA-2,5,11-TRIENE

The alcohol prepared in 1G (0.33 g, 1.09 mmoles) was dissolved in drymethylene chloride (5 ml). The mixture was cooled to 0° C. and1-chloro-N,N',2-trimethylpropenylamine (0.147 g, 1.1. mmoles) was added.The mixture was stirred under argon for 15 min. Methylene chloride wasevaporated under reduced pressure. Flash chromatography on silica geland elution with pentene afforded the expected chloride as an oil (0.321g, 90%).

1I) PREPARATION OF 5,8-DIFLUOROEICOSA-5,8,14-TRIENAL

To a solution of N-allyl-N,N',N"-pentamethyl phosphoramide (0.20 g, 1mmoles) in tetrahydrofuran (10 ml) cooled to -78° C. was added dropwisen-butyllithium 1.32M in hexane (0.75 ml, 1 mmole). The mixture wasstirred under argon at -78° C. for 1 hr. To the resulting red-orangesolution, the chloride prepared in 1H in tetrahydrofuran (2 ml) wasadded dropwise at -78° C. The mixture was stirred for 1 hr. at -78° C.,then warmed to 0° C. within 2 hrs. and stirred 30 min. at 0° C. Thereaction was quenched with saturated aqueous ammonium chloride andtetrahydrofuran was evaporated under reduced pressure. The resulting oilwas diluted with methylene chloride and washed with water. The organiclayer was dried over magnesium sulfate. Filtration and concentrationunder reduced pressure afforded an oil. This oil was dissolved in ether(15 ml) and was stirred at room temperature during 2 hrs. with 2Naqueous solution of hydrochloric acid (15 ml). The organic layer waswashed twice with water, dried over magnesium sulfate, filtered andconcentrated under reduced pressure to afford an oil. Flashchromatography on silica gel and elution with a 25:75 mixture of ethylacetate and hexane afforded the desired aldehyde (0.21 g, 69%) as anoil.

1J) PREPARATION OF 5,8-DIFLUOROEICOSA-5,8,14-TRIENOIC ACID

To a solution of the aldehyde prepared in 1I (0.2 g, 0.61 mmoles) inacetone (7 ml) cooled to 0° C. was added dropwise 2.67M Jones reagentuntil the orange color was stable. The mixture was stirred 15 min. at 0°C. The excess of Jones reagent was reacted with isopropanol. The acetonewas evaporated under reduced pressure without heating. The residue wastaken with water and extracted three times with ethyl acetate. Theorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure to leave an oil. Flash chromatography on silicagel and elution with a 25:75 mixture of ethyl acetate and hexaneafforded the expected acid as an oil (0.125 g, 60%).

EXAMPLE 2 PREPARATION OF 5,9-DIFLUOROEICOSATETRAENOIC ACID

2A) PREPARATION OF FLUOROMALEIC ACID DIMETHYL ESTER

Fluoromaleic acid (37.14 g, 0.277 mole) were esterified in ether at 0°C. by an excess of 0.5M etheral solution of diazomethane until theyellow coloration was stable. Evaporation of the solvent afforded purediester as an oil (44.71 g, 99.5%). NMR (H¹, CDCl₃, 60MHz): 3.78 (s, 3),3.86 (s, 3), 6.06 (d, J_(HF) ═15.5 Hz, 1).

2B) PREPARATION OF (E) 1,3-DIHYDROXY-2-FLUORO-2-BUTENE

To a solution of the diester prepared in 2A (20 g, 0.123 mole) in drytetrahydrofuran (250 ml) cooled to -10° C. was added dropwise underargon a 1.2M diisobutyl aluminium hydride (DIBAL) in hexane (568 ml)while the temperature of the reaction mixture was maintained at 0° C.The mixture was stirred at 0° C. during one hour and during 1 hour atroom temperature. The mixture was cooled again to 0° C. and methanol (25ml) was added dropwise to destroy the excess of DIBAL. Then thealuminium salts were precipitated with an aqueous saturated solution ofammonium chloride added until a filtrable product was obtained. Thewhite-grey solid was filtered and the cake was washed with ethyl acetatecontaining 10% of methanol. The solvents were evaporated under reducedpressure. The resulting oil was chromatographed on silicagel using pureethyl acetate as eluent. The diol was obtained as an oil (5.4 g, 41%)NMR (H¹, CD₃ OD, 360 MHz): 4.13 (dd, J_(HH) ═8 Hz, J_(HF) ═1.5 Hz, 2),4.23 (d, J_(HF) ═21 Hz, 2), 5.43 (dt, J_(HF) ═20 Hz, J_(HH) ═8 Hz, 1).

2C) PREPARATION OF (E)1-CHLORO-3-FLUORO-4-(2-TETRAHYDROPYRANYLOXY)-2-BUTENE

To a solution of N-chlorosuccinimide (2.76 g, 18 mmoles) in methylenechloride (80 ml) was added to 0° C. dimethylsulfide (1.32 ml, 18 mmoles)and the mixture was stirred for 15 min at 0° C. Then after cooling at-25° C. the diol from 1B (1.74 g, 16.4 mmoles) in methylene chloride (40ml) was added dropwise. The mixture was stirred successively for 30 minat -25° C., 3 hours at 0° C., and finally 30 min at room temperature.Dihydropyran (3 ml, 32.8 mmoles) and pyridinium paratoluenesulfonate(430 mg, 1.6 mmoles) were added. Thus the mixture was stirred overnightat room temperature. The reaction mixture was washed with water andsaturated brine. The organic phase was dried over sodium sulfate.Filtration and flash chromatography on silicagel and elution with a 9:1mixture of hexane and ethyl acetate afforded the title chloride as anoil (2.69g, 79%). NMR (H¹, CDCl₃, 60MHz): characteristic peaks 4.15 (dd,J_(HH) ═8 Hz, J_(HF) ═1 Hz, 2), 4.23 (d, J_(HF) ═20 Hz, 2), 4.68 (broads,1), 5.55 (dt, J_(HH) ═8 Hz J_(HF) ═20 Hz, 1).

2D) PREPARATION OF (E)1-(1,3-DITHIA-2-CYCLOHEXYL-3-FLUORO-4-(2-TETRAHYDROPYRANYLOXY)-2-BUTENE)

To a solution of 1,3-dithiane (1.55g, 12.9 mmole) in tetrahydrofuran (60ml) cooled to -30° C. was added dropwise a 1.32M solution ofn-butyllithium in hexane (9.77 ml, 12.9 mmoles), the mixture was stirredat -30° C. for 30 min. Then the mixture was cooled to -40° C. and thechloride prepared in 1C (2.69 g, 12.9 mmoles) in tetrahydrofuran (10 ml)was added dropwise. The reaction was stirred 30 min at -40° C. and 2 hrsat 0° C. The reaction was quenched with saturated aqueous ammoniumchloride and the tetrahydrofuran was evaporated under reduced pressure.The residue was diluted with ether and washed with water. The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. Flash chromatography on silicagel and elution with a8:2 mixture of hexane and ethyl acetate afforded the title dithialane asan oil (3.34 g, 90%). NMR (H¹, CDCl₃, 60MHz) characetristic peaks: 4.00(t, J_(HH) ═7 Hz, 1), 4.21 (d, J_(HF) ═20 Hz, 2), 4.7 (broad peak, 1),5.40 (dt, J_(HF) ═20 Hz, J_(HH) ═8 Hz, 1).

2E) PREPARATION OF (E)1-(1,3-DITHIA-2-CYCLOHEXYL)-3-FLUORO-4-OL-2-BUTENE

The tetrahydropyranyl derivative prepared in 2D was dissolved inmethanol. Pyridinium para-toluene sulfonate (0.3 g, 1.2 mmoles) wasadded and the mixture was refluxed for 2.5 hrs. Methanol was evaporatedunder reduced pressure. The residue was dissolved in ether and washedwith water. The organic layer was dried over sodium sulfate, filteredand concentrated under reduced pressure. Flash chromatography onsilicagel and elution with a 1:1 mixture of hexane and ethyl acetateafforded the title alcohol as white crystals (2.11 g, 91%).Recrystallization in a mixture of hexane and ether afforded analyticallypure samples, m.p.=33.5°-34.5° C. NMR (H¹, CDCl₃, 60MHz) characteristicpeaks: 4.0 (t, J_(HH) ═7 Hz, 1), 4.18 (d, J_(HF) ═20 Hz, 2), 5.25 (dt,J_(HF) ═20 Hz, J_(HH) ═8 Hz, 1). Anal. Calc. for C₈ H₁₃ FOS₂ : C, 46.13;H, 6.29. Found: C, 46.28; H, 6.01).

2F) PREPARATION OF (E)4-CHLORO-2-(1,3-DITHIA-2-CYCLOHEXYL)-3-FLUORO-2-BUTENE

The alcohol prepared in 2E (1.9 g, 9.13 mmoles) was dissolved in drymethylene chloride (70 ml). The mixture was cooled to 0° C. and 1-chloroN,N',2-trimethylpropenylamine (1.23 g, 9.2 mmoles) was added. Themixture was stirred under argon for 15 min. Methylene chloride wasevaporated under reduced pressure. Flash chromatography on silicagel andelution with a 9:1 mixture of hexane and ethyl acetate afforded theexpected chloride as an oil (1.98 g, 96%). NMR (H¹, CDCl₃, 60MHz)characteristic peaks 4.05 (t, J_(HH) ═7 Hz, 1), 4.13 (d, J_(HF) ═21 Hz,2), 5.36 (dt, J_(HF) ═18 Hz J_(HH) ═8 Hz, 1).

2G) PREPARATION OF (E) 7-(1,3-DITHIA-2-CYCLOHEXYL)-5-FLUORO-5-HEPTENAL

To a solution of N-allyl-N, N',N"-pentamethyl phosphoramide (1.5 g, 7.32mmoles) in tetrahydrofuran (21 ml) cooled to -78C was added dropwisen-butyllithium 1.32M in hexane (5.55 ml, 7.32 mmoles). The mixture wasstirred under argon at -78° C. for 1 hr. To the resulting red-orangesolution, the chloride prepared in 2F in tetrahydrofuran (10 ml) wasadded dropwise at -78° C. The mixture was stirred for 1 hr at -78° C.,then warmed to 0° C. within 2 hrs and stirred 30 min at 0° C. Thereaction was quenched with saturated aqueous ammonium chloride andtetrahydrofuran was evaporated under reduced pressure. The resulting oilwas diluted with methylene chloride and washed with water. The organiclayer was dried over magnesium sulfate. Filtration and concentrationunder reduced pressure afforded an oil. This oil was dissolved in ether(36.5 ml) and was stirred at room temperature during 2 hrs with 2Naqueous solution of hydrochloric acid (36.5 ml). The organic layer waswashed twice with water, dried over magnesium sulfate, filtered andconcentrated under reduced pressure to afford an oil (1.45 g). Flashchromatography on silicagel and elution with a 25:75 mixture of ethylacetate and hexane afforded the desired aldehyde (1.014 g, 56%) as anoil. NMR (H¹, CDCl₃, 60MHz) characteristic peaks: 4.01 (t, J_(HH) ═7 Hz,1), 5.13 (dt, J_(HF) ═21 Hz, J_(HH) ═7 Hz, 1), 9.4 (t, J_(HH) ═1 Hz, 1).

2H) PREPARATION OF (E) 7-(1,3-DITHIA-2-CYCLOHEXYL)-5-FLUORO-5-HEPTENOL

The aldehyde prepared in 2G (0.937 g, 3.77 mmoles) was dissolved inmethanol (20 ml) and cooled to 0° C. Sodium borohydride (0.071 g, 1.87mmoles) was added and the mixture was stirred 30 min. Acetone was addedto react with an excess of sodium borohydride and then the reactionmixture was acidified with acetic acid. The solvents were evaporatedunder reduced pressure. The residue was diluted with ether and washedwith water. The organic phase was dried over sodium sulfate, filteredand concentrated under reduced pressure to afford the title alcohol asan oil in a quantitative yield. NMR (H¹, CDCl₃, 60MHz) characteristicpeaks 4 (t, J_(HH) ═7 Hz, 1), 5.1 (dt, J_(HF) ═21 Hz, J_(HH) ═8 Hz, 1).

2I) PREPARATION OF (E)1-(t-BUTYLDIPHENYLSILYLOXY)-7-(1,3-DITHIA-2-CYCLOHEXYL)-5-FLUORO-5-HEPTENE

To a solution of the alcohol prepared in 2H (2.15 g, 9.26 mmoles) in drymethylene chloride (50 ml) was added triethylamine (2 ml, 14.3 mmoles),t-butyldiphenylchlorosilane (2.65 ml, 10.2 mmoles) anddimethylaminopyridine (45 mg). The mixture was stirred overnight at roomtemperature. The reaction mixture was washed once with water and thendried over sodium sulfate. Filtration and evaporation under reducedpressure afforded an oil. Flash chromatography on silicagel and elutionwith a 8:92 mixture of ethyl acetate and hexane afforded the desiredsilylether as an oil (4.12 g, 94%). NMR (H¹, CDCl₃, 60MHz)characteristic peaks 1.06 (s, 9), 3.96 (t, J_(HH) ═7 Hz, 1), 5.06 (dt,J_(HF) ═21 Hz J_(HH) ═8 Hz, 1), 7.23 to 7.80 (m, 10).

2J) PREPARATION OF (E) 8-(t-BUTYLDIPHENYLSILYLOXY)-4-FLUORO-3-OCTENAL

To a suspension of trimethyloxonium tetrafluoroborate (0.44 g, 2.97mmoles) in dry methylene chloride (15 ml) was added at room temperaturethe dithialane prepared in 1I (1.45 g, 2.97 mmoles) and the mixture wasstirred for 1 hr. Then a 9:1 mixture of acetone and water (5 ml)containing calcium carbonate (0.6 g, 5.94 mmoles) was added and themixture was stirred overnight at room temperature. The precipitate wasfiltered off and after dilution with saturated brine the mixture wasextracted three times with ether. The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure toafford the expected aldehyde as an oil which was used after drying underhigh vacuum (1.19 g, 88%).

2K) PREPARATION OF ETHYL 2,6-DIFLUORO-10-DIPHENYL t-BUTYL SILYLOXYDECANE-2,5-DIENEOATE

n-BuLi 1.5M in hexane solution (4.3 ml) was added at -78° C. to asolution of diisopropylamine (0.9 ml) in tetrahydrofuran (25 ml). Themixture was stirred during 20 min. at -78° C. Thentriethylphosphonofluoro acetate (1.52 g, 6.28 mmoles) in tetrahydrofuran(3 ml) was added dropwise. The mixture was stirred 5 min. at -78° C. andthen 20 min. at 0° C. Then(E)-8-(t-butyldiphenylsilyloxy)-4-fluoro-3-octenal (2.5 g, 6.28 mmoles)in tetrahydrofuran (3 ml) was added dropwise at -78° C. The reactionmixture was stirred overnight at 0° C. The mixture was hydrolyzed with asaturated aqueous solution of ammonium chloride and extracted withether. The organic layer was washed with saturated brine, dried oversodium sulfate and concentrated under reduced pressure. Flashchromatography on silica gel and elution with a 8:2 mixture of hexaneand ethyl acetate afforded the expected ester as an oil (1.97 g, 61%).

2L) PREPARATION OF (E,E)-2,6-DIFLUORO-10-DIPHENYL t-BUTYLSILYLOXYDECANE-2,5-DIENE-OL

The ester prepared in 2K (1.97 g, 3.83 mmoles) in anhydrous ether (5 ml)was added at -78° C. to a mixture of DIBAL, 1M solution in hexane, (7.7ml, 7.7 mmoles) and ether (25 ml). The mixture was stirred 30 min. at-78° C., then overnight at room temperature. The excess of DIBAL wasdestroyed with methanol (2 ml) and the aluminum salts were precipitatedwith an aqueous saturated solution of ammonium chloride until afiltrable precipitate is obtained. The mixture was filtrated and theprecipitate washed with ethyl acetate. The solvents were evaporatedunder reduced pressure. Flash chromatography over silica gel and elutionwith a 8:2 mixture of hexane and ethyl acetate afforded the expectedalcohol as an oil (1.65 g, 91%).

2M) PREPARATION OF (E,E)-BROMO-2,6-DIFLUORO-10-DIPHENYLt-BUTYLSILYLOXYDECANE-2,5-DIENE

The alcohol prepared in 2L (1.65 g, 3.5 mmoles) was dissolved in drymethylene chloride (1.0 ml). The mixture was cooled to 0° C. and 1-bromoN,N',2-trimethylpropenylamine (0.63 g, 3.5 mmoles) was added. Themixture was stirred under argon for 30 min. The methylene chloride wasevaporated under reduced pressure. Flash chromatography on silica geland elution with a mixture of hexane and ethyl acetate (98:2) affordedthe expected bromide as an oil (1.82 g, 97%).

2N) PREPARATION OF(E,E)-1-(1,3-DITHIA-2-CYCLONYL)-2,6-DIFLUORO-10-DIPHENYLt-BUTYLSILYLOXYDECANE-2,5-DIENE

To a solution of 1,3-dithiane (0.42 g, 3.5 mmoles) in tetrahydrofuran(50 ml) cooled to -25° C. was added dropwise a 1.5M solution ofn-butyllithium in hexane (12.2 ml, 3.4 mmoles). The mixture was stirredat -30° C. for 30 min. Then the mixture was cooled to -40° C. and thebromide prepared in 2C (1.82 g, 3.4 mmoles) in tetrahydrofuran (10 ml)was added dropwise. The reaction was stirred 30 min at 40° C. and 2 hrs.at 0° C. The reaction was quenched with saturated aqueous ammoniumchloride and the tetrahydrofuran was evapoerated under reduced pressure.The residue was diluted with ether and washed with water. The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. Flash chromatography on silica gel and elution with a8:2 mixture of hexane and ethyl acetate afforded the title dithialane asan oil (1.58 g, 81 %).

2O) PREPARATION OF (E,E)-3,7-DIFLUORO-11-DIPHENYLt-BUTYLSILYLOXYUNDECANOL-3,6-DIENE

To a suspension of trimethyloxonium tetrafluoroborate (0.41 g, 2.75mmoles) in dry methylene chloride (75 ml) was added at room temperaturethe dithialane prepared in 2D (1.58 g, 2.75 mmoles) and the mixture wasstirred for 1 hr. Then a 9:1 mixture of acetone and water (5 ml)containing calcium carbonate (0.6 g, 5.94 mmoles) was added and themixture was stirred overnight at room temperature. The precipitate wasfiltered off and after dilution with saturated brine the mixture wasextracted three times with ether. The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure toafford an oil. The resulting oil was dissolved in ethanol (5 ml) andsodium borohydride (56 mg, 1.48 mmoles) was added. The mixture wasstirred 30 min. at 0° C. The excess of sodium borohydride was reactedwith acetone. The mixture was acidified with acetic acid andconcentrated under reduced pressure. The residue was taken with waterand extracted three times with ether. The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure toafford an oil. Flash chromatography on silica gel and elution with a28:72 mixture of ethyl acetate and hexane afforded the title alcohol asan oil (1.02 g, 75%).

2P) PREPARATION OF (E,E) 1-BROMO-3,7-DIFLUORO-11-DIPHENYLt-BUTYLSILYLOXYUNDECANE-3,6-DIENE

The alcohol prepared in 20 (1.02 g, 2.1 mmoles) was dissolved in drymethylene chloride (10 ml). The mixture was cooled to 0° C. and1-bromo,N,N',2-trimethylpropenylamine (0.374 g, 2.1 mmoles) was added.The mixture was stirred under argon for 15 min. Methylene chloride wasevaporated under reduced pressure. Flash chromatography on silica geland elution with a 95:5 mixture of hexane and ethyl acetate afforded theexpected bromide as an oil (1.098 g, 95%).

2Q) PREPARATION OF (E,E)-3,7-DIFLUORO-11-DIPHENYLt-BUTYLSILYLOXY)UNDECANYL-3,6-DIENE TRIPHENYLPHOSPHONIUM BROMINE

A mixture of the bromide prepared in 2P (1.098 g, 2 mmoles) andtriphenylphosphine (0.53 g, 2 mmoles) in dry acetonitrile (10 ml) wererefluxed for 48 hrs. Evaporation of the solvent under reduced pressure,flash chromatography on silica gel and elution with a 9:1 mixture ofmethylene chloride and methanol afforded the expected phosphoniumbromide as a foam (1.535 g, 90%).

2R) PREPARATION OF 5,9-DIFLUORO-1-(DIPHENYLt-BUTYLSILYLOXY-5,8,11,14-EICOSATETRAENE

To a solution of diisopropylamine (0.25 ml, 1.8 mmoles) intetrahydrofuran (15 ml) cooled -78° C. was added dropwise n-butyllithium1.6M in hexane solution (1.12 ml, 1.8 mmoles). The mixture was warmed to-10° C. and then cooled again to -78° C. The phosphonium bromideprepared in 2G (1.53 g, 1.8 mmoles) in tetrahydrofuran (5 ml) was addeddropwise and the mixture was stirred 30 min. at -78° C.Hexamethylphosphonictriamide (0.8 ml) was added and the reaction mixturewas warmed to -30° C. 2,3-Nonenal (0.252 g, 1.8 mmole) intetrahydrofuran (3 ml) was added dropwise and the mixture was stirred 2hrs. at -30° C. and 30 min. at 0° C. Saturated aqueous solution ofammonium chloride was added and tetrahydrofuran was evaporated underreduced pressure. The residue was taken up with water and extractedthree times with ether. The organic layer was washed twice with waterand dried over sodium sulfate. Filtration and evaporation of the solventafforded an oil. Flash chromatography on silica gel and elution with a9:1 mixture of hexane and benzene afforded the expected triene (0.544 g,51%).

2S) PREPARATION OF 5,9-DIFLUOROEICOSATETRAENOL

To a solution of the silylether prepared in 2R (10.544 g, 0.92 mmole) intetrahydrofuran (10 ml) was added tetra-n-butylamonium fluoridetrihydrate (410 mg, 1.3 mmole). The mixture was stirred at roomtemperature for 2 hr. The solvent was evaporated under reduced pressure.The residue was dissolved in methylene chloride, washed with water anddried over sodium sulfate. Filtration and concentration under reducedpressure afforded an oil. Flash chromatography on silica gel and elutionwith a 15:95 mixture of ethyl acetate and benzene afforded the expectedalcohol as an oil (282 mg, 94%).

2T) PREPARATION OF 5,9-DIFLUOROEICOSATETRAENOIC ACID

To a solution of the alcohol prepared in 2I (282 mg, 0.86 mmoles) inacetone (7 ml) cooled to 0° C. was added dropwise 2.67M Jones reagentover 15 min. until the orange color was stable. The mixture was stirred15 min. at 0° C. The excess of Jones reagent was reacted withisopropanol. The acetone was evaporated under reduced pressure withoutheating. The residue was taken up with water and extracted three timeswith ethyl acetate. The organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure to leave an oil. Flashchromatography on silica gel and elution with a 15:85 mixture of ethylacetate and benzene gave pure acid (180 mg, 61%).

The dithialom 1 and the aldehyde 2 are described during the synthesis of6-fluoroarachidonic acid.

EXAMPLE 3 PREPARATION OF 6,9-DIFLUOROEICOSATETRAENOIC ACID

3A) PREPARATION OF (E) 6-FLUORO-7-(2-TETRAHYDROPYRANYLOXY)-5-HEPTENAL

To a solution of N-allyl-N,N'N"-pentamethylphosphoramide (2.50 g, 11.99mmoles) in tetrahydrofuran (30 ml) cooled to -78° C. was added dropwisen-butyllithium 1.55M in hexane (7.74 ml, 11.93 mmoles). The mixture wasstirred under argon at -78° C. for 1 hr. To the resulting red-orangesolution the chloride prepared in 1C in tetrahydrofuran (15 ml) wasadded dropwise at -78° C. The mixture was stirred for 1 hr at -78° C.,then warmed up to 0° C. within 2 hrs and stirred 1 hr at 0° C. Thereaction was quenched with saturated aqueous ammonium chloride and thetetrahydrofuran was evaporated under reduced pressure. The resulting oilwas diluted with methylene chloride and washed with water. The organiclayer was dried over magnesium sulfate. Filtration and concentrationunder reduced pressure afforded an oil. This oil was dissolved in ether(60 ml) and was stirred at room temperature for 2 hrs with a 2N aqueoussolution of hydrochloric acid (60 ml). The organic layer was washedtwice with water, dried over magnesium sulfate, filtered andconcentrated under reduced pressure to afford an oil (2.10 g). The NMRof the crude mixture showed that the THP has been mostly cleaved. To asolution of the crude oil in methylene chloride (100 ml) was addeddihydropyran (2.1 ml) and pyridinium paratoluene sulfonate (0.236 g) andthe mixture was stirred overnight at room temperature. The reactionmixture was washed with water. The organic layer was dried over sodiumsulfate. Filtration and concentration under reduced pressure afforded anoil (3 g). Flash chromatography on silicagel and elution with a 25:75mixture of ethyl acetate and hexane afforded the aldehyde (1.74 g, 64%)as an oil. NMR (H¹, CDCl₃, 360MHz) characteristic peaks: 4.18 (AB partof an ABX system, J_(H).sbsb.A_(H).sbsb.B ═13 Hz, J_(H).sbsb.A_(F) ═20.5Hz, J_(H).sbsb.B_(F) ═24.6 Hz, 2), 4.68 (t, J_(HH) ═3.4 Hz, 1), 5.25(dt, J_(HH) ═8.2 Hz, J_(HF) ═20.4 Hz, 1), 9.77 (t, J_(HH) ═1.5 Hz, 1).

3B) PREPARATION OF (E) 6-FLUORO-7,12-TETRAHYDROPYRANYLOXY)-5-HEPTANOL

The aldehyde prepared in 3A (1.34 g, 7.56 mmoles) was dissolved inmethanol (20 ml) and cooled to 0° C. Sodium borohydride (0.143 g, 3.78mmoles) was added and the mixture was stirred 30 min. Acetone was addedto react with the excess of sodium borohydride. The solvents wereevaporated under reduced pressure. The residue was diluted with etherand washed with water. The organic phase was dried over sodium sulfate,filtered and concentrated under reduced pressure to afford pure alcoholas an oil (1.66 g) which was used to the next step without purification.

3C) PREPARATION OF (E)1-(t-BUTYLDIPHENYLSILYLOXY)-6-FLUORO-7-(2-TETRAHYDROPYRANYLOXY)-5-HEPTENE

To a solution of the alcohol prepared in 3B (1.66 g, 7.15 mmoles) in drymethylene chloride (50 ml) was added triethylamine (1.7 ml, 11.34mmoles), t-butyldiphenylchlorosilane (1.7 ml, 8.31 mmoles) anddimethylaminopyridine (40 mg). The mixture was stirred overnight at roomtemperature. The reaction mixture was washed once with water and thendried over sodium sulfate. Filtration and evaporation under reducedpressure afforded an oil. Flash chromatography on silicagel and elutionwith a 10:90 mixture of ethyl acetate and hexane afforded the silyletheras an oil (2.87 g).

3D) PREPARATION OF (E)1-(t-BUTYLDIPHENYLSILYLOXY)-6-FLUORO-5-HEPTENE-7-OL

The tetrahydropyranyl derivative prepared in 3C (2.26 g, 4.8 mmoles) wasdissolved in methanol. Tetrabutyl-1,3-diisothiocyanatodistannoxane (30mg) was added and the mixture was refluxed for 24 hrs. Methanol wasevaporated under reduced pressure. The residue was dissolved in etherand washed with water. The organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure. Flash chromatographyon silicagel and elution with a 2:8 mixture of hexane and ethyl acetateafforded the alcohol as an oil (1.65 g, 92%).

3E) PREPARATION OF (E)7-BROMO-1-(t-BUTYLDIPHENYLSILYLOXY)-6-FLUORO-5-HEPTENE

The alcohol prepared in 3D (1.1 g, 2.85 mmoles) was dissolved in drymethylene chloride (20 ml). The mixture was cooled to 0° C. and1-bromo,N,N',2-trimethylpropenylamine (0.51 g, 2.85 mmoles) was added.The mixture was stirred under argon for 15 min. Methylene chloride wasevaporated under reduced pressure. Flash chromatography on silicagel andelution with a 95:5 mixture of hexane and ethyl acetate afforded theexpected bromide as an oil (1.24 g, 98%). NMR (H¹, CDCl₃, 60 MHz)characteristic peaks: 1.05 (S, 9), 3.65 (m, 2), 3.91 (d, J_(HF) ═22 Hz,2), 5.23 (dt, J_(HF) ═19 Hz, J_(HH) ═7.5 Hz, 1), 7.26 to 7.78 (m, 10).

3F) PREPARATION OF(E)-1-(t-BUTYLDIPHENYLSILYLOXY)-7-(1,3-DITHIA-2-CYCLOHEXYL)-6-FLUORO-5-HEPTENE

To a solution of dithialane (0.365 g, 3.04 mmole) in tetrahydrofuran (50ml) cooled to -30° C. was added dropwise a 1.5M solution ofn-butyllithium in hexane (2 ml, 3 mmoles) and the mixture was stirred at-30° C. for 30 min. Then the mixture was cooled to -40° C. and thebromide prepared in 3E (1.24 g, 2.76 mmoles) in tetrahydrofuran (10 ml)was added dropwise. The reaction was stirred 30 min at -40° C. and 2 hrsat 0° C. and then quenched with saturated aqueous ammonium chloride andthe tetrahydrofuran was evaporated under reduced pressure. The residuewas diluted with ether and washed with water. The organic layer wasdried over sodium sulfate, filtered and concentrated under reducedpressure. Flash chromatography on silicagel and elution with a 95:5mixture of hexane and ethyl acetate afforded the desired dithialane asan oil (0.524 g, 40%). NMR (H¹, CDCl₃, 60MHz) characteristic peaks: 1.03(s, 9), 3.61 (m, 2), 4.23 (t, J_(HH) ═7.5 Hz, 1), 5.3 (dt, J_(HF) ═21Hz, J_(HH) ═7.5 Hz, 1), 7.16 to 7.83 (m, 10).

3G) PREPARATION OF (E) 8-(t-BUTYLDIPHENYLSILYLOXY)-3-FLUORO-3-OCTENAL

To a solution of the dithialane prepared in 3F (0.424 g, 0.86 mmoles) indry methylene chloride (4 ml) was added at room temperaturetrimethyloxonium tetrafluoroborate (0.125 g, 0.86 mmoles) and themixture was stirred for 1 hr. Then a 9:1 mixture of acetone and water (2ml) containing calcium carbonate (0.172 g, 1.72 mmoles) was added andthe mixture was stirred overnight at room temperature. The precipitatewas filtered off and after dilution with saturated brine the mixture wasextracted three times with ether. The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure toafford the expected aldehyde as an oil which was used after drying underhigh vacuum (0.366 g, 92%).

3H) PREPARATION OF ETHYL 2,5-DIFLUORO-10-DIPHENYL t-BUTYLSILYLOXYDECANE-2,5-DIENEOATE

n-BuLi 1.5M in hexane solution (4.3 ml) was added at -78° C. to asolution of diisopropylamine (0.9 ml) in tetrahydrofuran (25 ml). Themixture was stirred during 20 min. at -78° C. Thentriethylphosphonofluoro acetate (1.52 g, 6.28 mmoles) in tetrahydrofuran(3 ml) was added dropwise. The mixture was stirred 5 min. at -78° C. andthen 20 min. at 0° C. Then (E)8-(t-butyldiphenylsilyloxy)-3-fluoro-3-octenal (2.5 g, 6.28 mmoles) intetrahydrofuran (3 ml) was added dropwise at -78° C. The reactionmixture was stirred overnight at 0° C. The mixture was hydrolyzed with asaturated aqueous solution of ammonium chloride and extracted withether. The organic layer was washed with saturated brine, dried oversodium sulfate and concentrated under reduced pressure. Flashchromatography on silica gel and elution with a 8:2 mixture of hexaneand ethyl acetate afforded the expected ester as an oil (1.97 g, 61%).

3I) PREPARATION OF (E,E)-2,5-DIFLUORO-10-DIPHENYLt-BUTYLSILYLOXYDECANE-2,5-DIENEOL

The ester prepared in 3H (1.97 g, 3.83 mmoles) in anhydrous ether (5 ml)was added at -78° C. to a mixture of DIBAL, 1M solution in hexane, (7.7ml, 7.7 mmoles) and ether (25 ml). The mixture was stirred 30 min. at-78° C., then overnight at room temperature. The excess of DIBAL wasdestroyed with methanol (2 ml) and the aluminum salts were precipitatedwith an aqueous saturated solution of ammonium chloride until afiltrable precipitate is obtained. The mixture was filtrated and theprecipitate washed with ethyl acetate. The solvents were evaporatedunder reduced pressure. Flash chromatography over silica gel and elutionwith a 8:2 mixture of hexane and ethyl acetate afforded the expectedalcohol 3 as an oil (1.65 g, 91%).

3J) PREPARATION OF (E,E)-BROMO-2,5-DIFLUORO-10-DIPHENYLt-BUTYLSILYLOXYDECANE-2,5-DIENE

The alcohol prepared in 3I (1.65 g, 3.5 mmoles) was dissolved in drymethylene chloride (1.0 ml). The mixture was cooled to 0° C. and 1-bromoN,N',2-trimethylpropenylamine (0.63 g, 3.5 mmoles) was added. Themixture was stirred under argon for 30 min. The methylene chloride wasevaporated under reduced pressure. Flash chromatography on silica geland elution with a mixture of hexane and ethyl acetate (98:2) affordedthe expected bromide as an oil (1.82 g, 97%).

3K) PREPARATION OF(E,E)-1-(1,3-DITHIA-2-CYCLOHEPTYL)-2,5-DIFLUORO-10-DIPHENYLt-BUTYLSILYLOXYDECANE-2,5-DIENE

To a solution of 1,3-dithiane (0.42 g, 3.5 mmoles) in tetrahydrofuran(50 ml) cooled to -25° C. was added dropwise a 1.5M solution ofn-butyllithium in hexane (12.2 ml, 3.4 mmoles). The mixture was stirredat -30° C. for 30 min. Then the mixture was cooled to -40° C. and thebromide prepared in 3J (1.82 g, 3.4 mmoles) in tetrahydrofuran (10 ml)was added dropwise. The reaction was stirred 30 min at 40° C. and 2 hrs.at 0° C. The reaction was quenched with saturated aqueous ammoniumchloride and the tetrahydrofuran was evapoerated under reduced pressure.The residue was diluted with ether and washed with water. The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. Flash chromatography on silica gel and elution with a8:2 mixture of hexane and ethyl acetate afforded the title dithialane asan oil (1.58 g, 81 %).

3L) PREPARATION OF (E,E)-3,6-DIFLUORO-11-DIPHENYLt-BUTYLSILYLOXYUNDECANOL-3,6-DIENE

To a suspension of trimethyloxonium tetrafluoroborate (0.41 g, 2.75mmoles) in dry methylene chloride (75 ml) was added at room temperaturethe dithialane prepared in 3D (1.58 g, 2.75 mmoles) and the mixture wasstirred for 1 hr. Then a 9:1 mixture of acetone and water (5 ml)containing calcium carbonate (0.6 g, 5.94 mmoles) was added and themixture was stirred overnight at room temperature. The precipitate wasfiltered off and after dilution with saturated brine the mixture wasextracted three times with ether. The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure toafford an oil. The resulting oil was dissolved in ethanol and sodiumborohydride (56 mg, 1.48 mmoles) was added. The mixture was stirred 30min. at 0° C. The excess of sodium borohydride was reacted with acetone.The mixture was acidified with acetic acid and concentrated underreduced pressure. The residue was taken with water and extracted threetimes with ether. The organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure to afford an oil. Flashchromatography on silica gel and elution with a 28:72 mixture of ethylacetate and hexane afforded the title alcohol as an oil (1.02 g, 75%).

3M) PREPARATION OF (E,E)-1 -BROMO-3,6-DIFLUORO-11-DIPHENYLt-BUTYLSILYLOXYUNDECANE-3,6-DIENE

The alcohol prepared in 3L (1.02 g, 2.1 mmoles) was dissolved in drymethylene chloride (10 ml). The mixture was cooled to 0° C. and1-bromo,N,N',2-trimethylpropenylamine (0.374 g, 2.1 mmoles) was added.The mixture was stirred under argon for 15 min. Methylene chloride wasevaporated under reduced pressure. Flash chromatography on silica geland elution with a 95:5 mixture of hexane and ethyl acetate afforded theexpected bromide as an oil (1.098 g, 95%).

3N) PREPARATION OF (E,E)-3,6-DIFLUORO-11-DIPHENYLt-BUTYLSILYLOXY)UNDECANYL-3,6-DIENE TRIPHENYLPHOSPHONIUM BROMINE

A mixture of the bromide prepared in 3M (1.098 g, 2 mmoles) andtriphenylphosphine (0.53 g, 2 mmoles) in dry acetonitrile (10 ml) wererefluxed for 48 hrs. Evaporation of the solvent under reduced pressure,flash chromatography on silica gel and elution with a 9:1 mixture ofmethylene chloride and methanol afforded the expected phosphoniumbromide as a foam (1.535 g, 90%).

3O) PREPARATION OF 6,9-DIFLUORO-1-(DIPHENYLt-BUTYLSILYLOXY-5,8,11,14-EICOSATETRAENE

To a solution of diisopropylamine (0.25 ml, 1.8 mmoles) intetrahydrofuran (15 ml) cooled to -78° C. was added dropwisebutyllithium 1.6M in hexane solution (1.12 ml, 1.8 mmoles). The mixturewas warmed to -10° C. and then cooled again to -78° C. The phosphoniumbromide prepared in 3G (1.53 g, 1.8 mmoles) in tetrahydrofuran (5 ml)was added dropwise and the mixture was stirred 30 min. at -78° C.Hexamethylphosphonictriamide (0.8 ml) was added and the reaction mixturewas warmed to -30° C. 2,3-Nonenal (0.252 g, 1.8 mmole) intetrahydrofuran (3 ml) was added dropwise and the mixture was stirred 2hrs. at -30° C. and 30 min. at 0° C. Saturated aqueous solution ofammonium chloride was added and tetrahydrofuran was evaporated underreduced pressure. The residue was taken up with water and extractedthree times with ether. The organic layer was washed twice with waterand dried over sodium sulfate. Filtration and evaporation of the solventafforded an oil. Flash chromatography on silica gel and elution with a9:1 mixture of hexane and benzene afforded the expected triene (0.544 g,51%).

3P PREPARATION OF 6,9-DIFLUOROEICOSATETRAENOL

To a solution of the silylether prepared in 30 (10.544 g, 0.92 mmole) intetrahydrofuran (10 ml) was added tetra-n-butylamonium fluoridetrihydrate (410 mg, 1.3 mmole). The mixture was stirred at roomtemperature for 2 hr. The solvent was evaporated under reduced pressure.The residue was dissolved in methylene chloride, washed with water anddried over sodium sulfate. Filtration and concentration under reducedpressure afforded an oil. Flash chromatography on silica gel and elutionwith a 15:95 mixture of ethyl acetate benzene afforded the expectedalcohol as an oil (282 mg, 94%).

3Q) PREPARATION OF 6,9-DIFLUOROEICOSATETRAENOIC ACID

To a solution of the alcohol prepared in 3P (282 mg, 0.86 mmoles) inacetone (7 ml) cooled to 0° C. was added dropwise 2.67M Jones reagentover 15 min. until the orange color was stable. The mixture was stirred15 min. at 0° C. The excess of Jones reagent was reacted withisopropanol. The acetone was evaporated under reduced pressure withoutheating. The residue was taken up with water and extracted three timeswith ethyl acetate. The organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure to leave an oil. Flashchromatography on silica gel and elution with a 15:85 mixture of ethylacetate and benzene gave pure acid (180 mg, 61%).

We claim:
 1. A fluorinated arachidonic acid derivatives of the formula##STR26## wherein one of R₅ and R₆ is a fluoro group and the other is ahydrogen or both R₅ and R₆ individually are a hydrogen;one of R₈ and R₉is a fluoro group and the other is a hydrogen, with the proviso thatwhen R₈ is a fluoro group, one of R₅ or R₆ is a fluoro group; X is aC(O)OR' group wherein R' is a hydrogen, a straight chain (C₁ -C₆)alkylgroup, or X is a group of the formula --C(O)OCH₂ CH(OR")CH₂ (OR'")wherein R" is a long chain fatty acid residue and wherein R"' is ahydrogen or a long chain fatty acid residue, or X is a --C(O)NH₂ or--C(O)NH(OH) group, or X is a 1H-tetrazol-5-yl group; and R is a groupof one of the structural formulae ##STR27## wherein R₃ is a hydrogen ora straight chain (C₁ -C₄)alkyl and R₄ is a hydrogen or a straight chain(C₁ -C₆)alkyl and wherein a dotted line indicates an optional double ortriple bondas well as where X is C(O)OR' and R' is a hydrogen or apharmaceutically acceptable salt thereof.
 2. A fluorinated arachidonicacid derivative of claim 1 wherein X is a CO₂ H group.
 3. A fluorinatedarachidonic acid derivative of one of claims 2 or 1 wherein X is a groupof the formula --C(O)OCH₂ CH(OR")CH₂ (OR"') wherein R" is a long chain,fatty acid residue and wherein R'" is a hydrogen or a long chain, fattyacid residue.
 4. A fluorinated arachidonic acid derivative of one ofclaims 2 or 1 wherein R is a group of the structural formula ##STR28##wherein R₃ is a hydrogen or a straight chain (C₁ -C₄)alkyl and wherein adotted line indicates an optional double or triple bond.
 5. Afluorinated arachidonic acid derivative of claim 4 wherein R₃ is anethyl group.
 6. A fluorinated arachidonic acid derivative of one ofclaims 2 or 1 wherein R is a group of the structural formula ##STR29##wherein R₃ is a hydrogen or a straight chain (C₁ -C₄)alkyl.
 7. Afluorinated arachidonic acid derivative of claim 6 wherein R₃ is anethyl group.
 8. A method for inhibiting 5-lipoxygenase in a patient inneed thereof which comprises administering to the patient an effectiveamount of a compound of the formula ##STR30## wherein one of R₅ and R₆is a fluoro group and the other is a hydrogen or both R₅ and R₆individually are a hydrogen;one of R₈ and R₉ is a fluoro group and theother is a hydrogen, with the proviso that when R₈ is a fluoro group,one of R₅ or R₆ is a fluoro group; X is a C(O)OR' group wherein R' is ahydrogen, a straight chain (C₁ -C₆)alkyl group, or X is a group of theformula --C(O)OCH₂ CH(OR")CH₂ (OR'") wherein R" is a long chain fattyacid residue and wherein R'" is a hydrogen or a long chain fatty acidresidue, or X is a --C(O)NH₂ or --C(O)NH(OH) group, or X is a1H-tetrazol-5-yl group; and R is a group of one of the structuralformulaewherein R₃ is a hydrogen or a straight chain (C₁ -C₄ -alkyl andR₄ is a hydrogen or a straight chain (C₁ -C₆)alkyl and wherein a dottedline indicates an optional double or triple bondas well as where X isC(O)OR' and R' is a hydrogen or a pharmaceutically acceptable saltthereof.
 9. A method of claim 8 wherein X is a CO₂ H group.
 10. A methodof one of claims 9 or 8 wherein X is a group of the formula --C(O)OCH₂CH(OR")CH₂ (OR'") wherein R" is a long chain, fatty acid residue andwherein R"' is a hydrogen or a long chain, fatty acid residue.
 11. Amethod of one of claims 9 or 8 wherein R is a group of the structuralformula ##STR31## wherein R₃ is a hydrogen or a straight chain (C₁-C₄)alkyl and wherein a dotted line indicates an optional double ortriple bond.
 12. A method of claim 11 wherein R₃ is an ethyl group. 13.A method of claim one of claims 9 or 8 wherein R is a group of thestructural formula ##STR32## wherein R₃ is a hydrogen or a straightchain (C₁ -C₄)alkyl.
 14. A method of claim 13 wherein R₃ is an ethylgroup.
 15. A method for the treatment of asthma in a patient in needthereof which comprises administering to the patient an effective amountof a compound of the formula:X is a --C(O)NH₂ or --C(O)NH(OH) group, orX is a 1H-tetrazol-5-yl group; and R is a group of one of the structuralformulae ##STR33## wherein R₃ is a hydrogen or a straight chain (C₁-C₄)alkyl and R₄ is a hydrogen or a straight chain (C₁ -C₆)alkyl andwherein a dotted line indicates an optional double or triple bondas wellas where X is C(O)OR' and R' is a hydrogen or a pharmaceuticallyacceptable salt thereof.
 16. A method of claim 15 wherein X is a CO₂ Hgroup.
 17. A method of one of claims 16 or 15 wherein X is a group ofthe formula --C(O)OCH₂ CH(OR")CH₂ (OR"') wherein R" is a long chain,fatty acid residue and wherein R"' is a hydrogen or a long chain, fattyacid residue.
 18. A method of one of claims 16 or 15 wherein R is agroup of the structural formula ##STR34## wherein R₃ is a hydrogen or astraight chain (C₁ -C₄)alkyl and wherein a dotted line indicates anoptional double or triple bond.
 19. A method of claim 18 wherein R₃ isan ethyl group.
 20. A method of claim one of claims 16 or 15 wherein Ris a group of the structural formula ##STR35## wherein R₃ is a hydrogenor a straight chain (C₁ -C₄)alkyl.
 21. A method of claim 20 wherein R₃is an ethyl group.